The pathogenesis of several diseases involve factors that increase the concentration of 3′5′-adenosine monophosphate (cAMP) in the tissues of humans and nonhuman animals. In mammalian cells this important intracellular mediator is formed by the conversion of adenosine triphosphate (ATP) to cAMP; the latter reaction is catalyzed by adenylyl cyclase. Bacterial cells also form cAMP catalyzed by a prokaryotic version of adenylyl cyclase.
An increase in tissue cAMP concentration is the key factor in numerous bacterial infections. For example, the bacterial toxins produced by Vibrio cholerae and many strains of enterotoxinogenic Escherichia coli (ETEC) stimulate intestinal epithelial cell adenylyl cyclase, evoking an increase in the intracellular and extracellular levels of cAMP (FIG. 1). The physiological consequence of this effect is the stimulatory impact of cAMP on the chloride, potassium, and sodium channels in the membranes of cells lining the lumen of the small intestine. The hypersecretion of chloride and other ions culminate in the accumulation of water and electrolytes in the intestinal lumen that ultimately becomes diarrhea. This is also known as cholera, in the case of V. cholerae and Tourista or Travelers diarrhea in the case of Escherichia coli. 
Other bacteria that evoke increases in tissue cAMP include Bordetella pertussis, the causative agent of whooping cough or Pertussis. These bacteria secrete two bacterial proteins that increase cAMP levels in the respiratory tract. One virulence factor is a bacterial adenylyl cyclase that is taken up by respiratory cells and converts respiratory ATP to cAMP. In addition, B. pertussis secretes pertussis toxin, which binds to respiratory cells and stimulates mammalian adenylyl cyclase in cells of the respiratory tract (Young and Collier, 2007). The physiological significance of these bacteria needing to increase cAMP in the respiratory tract is not entirely clear, but it is known that cAMP inhibits phagocytosis of bacteria by macrophages (mφ) and polymorphonuclear neutrophils (PMNs), which would limit the protection of the body against bacteria. Drugs that increase lung cAMP levels cause dilatation of the airways, which could facilitate the access to and colonization of the alveolar sacs. Since cAMP stimulates the expression of many mammalian cell genes, proteins thus formed could enhance the synthesis of tissue receptors for bacteria and their toxins.
Much of the tissue edema in patients infected with B. anthracis is attributed to the B. anthracis edema toxin, which is a combination of edema factor (EF) and protective antigen (PA). The latter protein binds the anthrax toxins to receptors on target cells in the lungs and many other tissues throughout the body (Firoved et al., 2005; Milne et al., 1995). Although all these examples are bacterial infections, some tumor types are known to hypersecrete prostaglandins (e.g., PGE2) that stimulate adenylyl cyclase in epithelial cells along the intestinal tract to form excessive amounts of cAMP. These patients have virtually continuous diarrhea. All possible uses of small molecules that inhibit adenylyl cyclase may not yet be obvious; however, many drugs used in the treatment of asthma patients work by increasing cAMP levels to open the airways. In patients over medicated with drugs like theophyline, a small molecule inhibitor of adenylyl cyclase could be used to neutralize excessive levels of cAMP. There may be multiple clinical uses for small molecules that inhibit adenylyl cyclase.
As described above, many pathogenic bacteria, regardless of their cellular morphology and grouping, produce toxins with similar functions that are often plasmid encoded. For example, Bacillus anthracis, a Gram-positive, spore-forming, rod-shaped bacterium, produces two types of factors that enhance its lethality, a polysaccharide capsule (Drysdale et al., 2005) and two protein toxins, lethal toxin (LT) and edema toxin (ET). Both toxins are lethal when injected into mice, and they suppress the functions of macrophages, polymorphopneutrophils, and lymphocytes. Thus, there is a need for toxin inhibitors as an adjunct to antibiotic treatment. One component of both toxins is protective antigen (PA), which enables the cell entry of the enzymatic toxin components lethal factor (LF) and edema factor (EF) (Abrami et al., 2005). LF contains metalloprotease activity that is specific for the MAP kinase proteins. An inhibitor of LF has been identified, and shown to be an effective adjunct to antibiotic therapy in animal studies (Xiong et al., 2006). This inhibitor does not affect the activity of EF, which is an adenylyl cyclase analogous to that produced by Bordetella pertussis (the causative agent of whooping cough) (Munier et al., 1992; Hewlett et al., 1979; Hewlett et al., 1976). These “adenylyl cyclase” toxins (Drum et al., 2002; Shen et al., 2005) catalyze the intracellular production of cAMP from ATP (Leppla, 1982; de Rooij et al., 1998; Lacy et al., 2002; Lacy et al., 2002). High levels of cAMP perturb the water homeostasis of the cell leading to abnormalities in the intracellular signaling pathways and chloride channel stimulation (Ajuha et al., 2004; Ascenzi et al., 2002; Peterson et al. 2001), This contributes to edema (and widening) of the mediastinum located between the lobes of the lungs of patients with inhalation anthrax. Patients with cutaneous anthrax often display tissue edema near the lesion. Inhibitors that would bind to EF and prevent its intracellular enzymatic activity could reduce the severity of infections by B. anthracis and other bacteria that produce similar toxins. Currently known cAMP inhibitors in the art are toxic (Soelaiman et al., 2003), demonstrating a need for the current invention.